Rat genome compared with human, mouse

An international research team has announced that it has completed a high-quality, draft sequence of the genome of the Brown Norway strain of the laboratory rat (Rattus norvegicus).

The Rat Genome Sequencing Project Consortium, led by the Human Genome Sequencing Center at Baylor College of Medicine in Houston, described its findings in the 1 April 2004 issue of the journal Nature.

For nearly 200 years, the laboratory rat has played a valuable role in efforts to understand human biology and to develop new and better drugs. Areas in which rat models have already helped to advance medical research include: cardiovascular diseases (hypertension); psychiatric disorders (studies of behavioral intervention and addiction); neural regeneration; diabetes; surgery;
transplantation; autoimmune disorders (rheumatoid arthritis); cancer; wound and bone healing; and space motion sickness.

In drug development, the rat is routinely employed to demonstrate therapeutic efficacy and assess toxicity of drug compounds prior to human clinical trials. The genome sequence will facilitate all of these studies, as well as help researchers better pinpoint the crucial areas of biological difference between rats and humans.

The rat sequence draft, which covers more than 90 per cent of the genome, represents the third mammalian genome to be sequenced to high quality and described in a major scientific publication. A draft of the human genome sequence was published in February 2001, and the completed human sequence was announced in April 2003. A draft of the mouse genome sequence was published in
December 2002. The availability of a third mammalian genome sequence gives scientists the ability to triangulate data to better resolve details of human biology, as well as mammalian evolution.

In their Nature paper, the researchers reported that, at approximately 2.75 billion base pairs, the rat genome is smaller than the human genome, which is 2.9 billion base pairs, and slightly larger than mouse genome, which is 2.6 billion base pairs. However, they also found that the rat genome contains about the same number of genes as the human and mouse genomes. Furthermore,
almost all human genes known to be associated with diseases have counterparts in the rat genome and appear highly conserved through mammalian evolution, confirming that the rat is an excellent model for many areas of medical research.

Comparison of the rat genome to those of the human and mouse also opens a new and unique window into mammalian evolution. The rodent lineage, which gave rise to the rat and mouse, and the primate lineage, which gave rise to humans, diverged about 80 million years ago.

Humans have 23 pairs of chromosomes, while rats have 21 and mice have 20. However, the new analysis found chromosomes from all three organisms to be related to each other by about 280 large regions of sequence similarity - called 'syntenic blocks' - distributed in varying patterns across the organisms' chromosomes.

The sequence data also confirms that the rodent lineage split 12 to 24 million years ago into the separate lines that gave rise to the rat and to the mouse. Researchers estimate about 50 chromosomal rearrangements occurred in each of the rodent lines after divergence from their common ancestor. The number of chromosomal rearrangements, as well as other types of genome changes,
was found to be much lower in the primate lineage, indicating that evolutionary change has occurred at a faster rate in rodents than in primates.

The new analysis also underscores the fact that while rats and mice look very similar to the human eye, there are significant genomic differences between the two types of rodents. For example, some aspects of genomic evolution in the rat appear to be accelerated when compared to the mouse. According to the new analysis, due to the unusually rapid expansion of selected gene
families, rats possess some genes not found in the mouse, including genes involved in immunity, the production of pheromones (chemicals involved in sexual attraction), the breakdown of proteins and the detection and detoxification of chemicals.